Template Letters to Facilitate Communications HTML to ensure appropriate dialogue between data users and generators and for authors to contact ICGC members and editors

Clinic & Pathology

Italy:

University of Pavia Medical School

Sweden:

Karolinska University Hospital

United Kingdom:

Cambridge Institute for Medical Research

John Radcliffe Hospital Oxford

St James's Institute of Oncology

Weatherall Institute of Molecular Medicine, University of Oxford

Wessex Regional Genetics Laboratory, Salisbury District Hospital

This group will collect and assess samples and clinical data from patients for inclusion in the study.

Sequencing & Analysis

United Kingdom:

Wellcome Trust Sanger Institute

Massively parallel sequencing technologies will be employed to generate high-depth coverage of genomic DNA extracted from myeloid cells and matched constitutional control samples. These data will be analysed bioinformatically in order to identify the differences between the cancer and a normal cell. The aim is to generate a high-quality compendium of all somatic mutations of all categories in 500 patients with chronic myeloid malignancies.

Complementary Studies

United Kingdom:

Wellcome Trust Sanger Institute

Complementary studies will include generation of genome-wide profiles for DNA methylation through methyl cap fractionation and gene expression profiling using shotgun tag sequencing (RNA-Seq). Chromatin- and DNA methylation-enriched tag sequencing (ChIP-seq, MethylCap-seq and MeDIP-seq) will also be carried out in selected cases, such as those patients receiving therapy with drugs targeting epigenetic pathways.

Data Storage, Analysis & Management

United Kingdom:

Wellcome Trust Sanger Institute

We will convert the summary datasets into ICGC compatible BioMart datasets.

Project Publications

Project Summary

The chronic myeloid disorders are a heterogeneous group of clonal or oligoclonal haematological disorders characterised by hyperproliferation of myeloid progenitor cells, cytopenias or cytoses and a risk of progression to acute leukaemia. Despite being the commonest group of haematological disorders, with a rapidly rising incidence in the West due to ageing population structures, treatment remains unsatisfactory, with most patients having few options other than supportive blood transfusions or cytoreductive therapy.

The majority of patients with myelodysplastic syndromes have normal cytogenetics and for most of the recurrent cytogenetic abnormalities, causative genes have not been identified. One exception is the 5q- syndrome, where haploinsufficiency of RPS14 is associated with impaired erythroid differentiation. Point mutation screens have documented mutations in KRAS, NRAS, JAK2, FLT3, TET2 and RUNX1, but generally at rates of <5-10% and often at late stages of the disease.

MDS is an interesting model for the effects of ageing on haematopoiesis. The basis for the selective outgrowth of MDS clones is unknown, but may reflect chronic DNA damage accumulated during ageing, causing premature senescence and depletion of normal haemopoietic stem cells with subsequent clonal immortalisation. The genomes of MDS cells may therefore bear the signature of environmental exposures and DNA damage acquired by haematopoietic stem cells throughout life.